Determination of muscarinic agonist potencies at M1 and M2 muscarinic receptors in a modified pithed rat preparation

Naunyn-Schmiedeberg's Archives of Pharmacology
P AngeliJ Wess

Abstract

The agonistic potencies of (+/-)muscarine, (+/-)cis-2-methyl-5- [(dimethylamino)methyl]-1,3-oxathiolane methiodide (cis-oxathiolane) and its two enantiomers were determined at muscarinic M1 and M2 receptors in the pithed rat. In non-pretreated animals, i.v. administration of these agents produced bradycardic effects mediated by cardiac M2 receptors followed by increases in heart rate mediated by M1 receptors in sympathetic ganglia. As these responses have been shown to partly overlap, "true" M1 and M2 potencies were determined after selective blockade of M1 and M2 receptors by pirenzepine and methoctramine, respectively. A similar rank order of agonist potencies was obtained at M1 and M2 receptors: (+)cis-oxathiolane greater than (+/-)cis-oxathiolane greater than (+/-)muscarine greater than (-)cis-oxathiolane. At both receptor subtypes, (+)cis-oxathiolane was considerably more potent (ca. 30-fold) than its corresponding (-) enantiomer indicating that the agonist binding sites of the two receptor subtypes may have similar stereochemical properties. While (+/-)muscarine showed similar potencies at M1 and M2 receptors, racemic cis-oxathiolane and its two enantiomers showed a slight selectivity (3-7 fold) for M1 receptors indicatin...Continue Reading

References

Apr 1, 1989·Trends in Neurosciences·T I Bonner
Sep 1, 1989·European Journal of Pharmacology·G LambrechtE Mutschler
Sep 1, 1988·Naunyn-Schmiedeberg's Archives of Pharmacology·J WessG Lambrecht
Jun 1, 1988·Trends in Pharmacological Sciences·C Melchiorre
May 5, 1986·Life Sciences·A GiachettiE Montagna
Apr 1, 1947·Proceedings of the Society for Experimental Biology and Medicine·R E SHIPLEY, J H TILDEN

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